Halfway through the fifth season of Tim & Eric's Awesome Show, Great Job!, Will Ferrell makes a cameo appearance in a spoof cable TV advert. As Donald Mahanahan, a specialist breeder and retailer of 'child clowns', Ferrell warns: "Never touch the clowns," his face twisted up using the cheapest post-production effects. "Let the clowns touch you," he adds, before hitting the caged toddlers dressed in clown outfits with a stick. As material goes, it's on the edge.

Despite having to put themselves in some of the most absurd and sometimes disturbing comedy situations imaginable, the rollcall of celebrities who have appeared in Tim Heidecker and Eric Wareheim's manic sketch show is impressive. It reads like a who's who of underground and mainstream US comedy: Ben Stiller, Jonah Hill, Rainn Wilson, Maria Bamford, Will Forte, Michael Cera, Fred Willard, Flight of the Conchords, Ted Danson and Bill Hader have all participated – several of them regularly.

Both Zach Galifianakis and John C Reilly are among the core cast members, Reilly playing talk show physician Dr Steve Brule, and Galifianakis appearing as, among other characters, Tairy Greene, a brutal child method acting teacher.

Yet there's a strong chance you've never heard of Tim and Eric. To their legion of devoted fans in the UK, they're a best-kept secret, sought out through online clips and a handful of DVD releases thanks to network Adult Swim. So how does a show which dips its toes so frequently into the mainstream stay so resolutely apart from it? And how come, if it's for Tim and Eric, a comedian with a mainstream profile like Will Ferrell can get away with playing a buck-toothed child molester?

"Most people would think, well this is a spoof of something," says Wareheim from their Los Angeles offices. "Of course Will Ferrell doesn't collect semen and insert it into clown ladies." Well, quite.

The pair met at Temple University's film school in Pennsylvania. "There's a lot of dopes in life, and in film school," says Heidecker. "The interesting people are usually easy to find." Some DVDs of their lo-fi animation show Tom Goes to the Mayor found their way to Bob Odenkirk, the writer and director behind cult US comedy Mr Show with Bob and David, which he starred in and wrote with David Cross. Odenkirk offered to produce it and it quickly gained a following, with the likes of Jack Black, Jeff Goldblum, Garry Shandling, Janeane Garofalo and Sarah Silverman playing guest roles.

"Back when we went to film school, there was no alternative comedy that we knew of," says Heidecker. "We didn't know about Mr Show, or [Chris Morris's post-Brass Eye project] Jam. What comedy was to us was just standup and this really corny, shitty shit that was popular. We grew up loving comedy, but to us it wasn't a viable thing that we could do as filmmakers. It wasn't very cool. It wasn't very smart. But we naturally gravitated that way."

It's apt that Heidecker should mention Jam, Morris's woozy sketch show, as inspiration. Awesome Show in particular has, at times, that same unsettling quality, though shot through with manic cable TV technicolour, Python-esque animation and purposely amateur editing. Both shows deal with absurdity and darkness in equal measure. In another Awesome Show sketch, a sinister salesman, played by Peter Stormare, gatecrashes the funeral of a child and offers the grieving mother a product he is hawking – a synthetic boy that can be replaced and last forever. It's dark, but it's also hard not to giggle at the extremity of it.

"I think the darkness grew in us, as time went on. There was always uncomfortableness and awkwardness, but not so much darkness," says Heidecker. "Our first entrance into doing this professionally was writing a weekly cartoon. It was a cartoon, so anything could happen, so a lot of awful, dark, fucked-up things happened, because they made us laugh. When you're doing 30 episodes of something, you start thinking: 'Well, what if he explodes?'"

But it's not all bleak by any means. Though Reilly's character Steve Brule is tragic, his Brules Rules skits are genuinely inspired, and you're never far away from a celebration of bodily fluids. Also unique to Heidecker and Wareheim's show is their use of amateur actors, a legion of whom they have employed over the years. Often looking baffled, they deliver their lines, perform songs and appear in spoof infomercials upstaging their famous counterparts, with regulars James Quall and puppeteer David Liebe Hart gaining a notoriety of their own. They are, as Heidecker describes them, "people you don't see on TV".

As you might expect, the big screen is beckoning. They've just finished shooting their debut feature film, Tim & Eric's Billion Dollar Movie, produced by Will Ferrell and Adam McKay's Gary Sanchez Productions. In a case of art imitating life, it follows Heidecker and Wareheim after they are given a billion dollars to make a movie (though the actual budget was seemingly a little less robust) and will feature all the Tim & Eric regulars, including Ferrell.

But perhaps more exciting to their UK fanbase is that they are bringing their live show to the UK for the first time. "This is big for us, because we've been getting written from you guys for years now, asking us to come over," says Wareheim. "It should almost feel like a homecoming, because so much of our show is clearly influenced by British sensibility, that it's funny we're coming to play to people who have helped established our style." As well as Jam, the pair have long had an open love-in with Robert Popper and Peter Serafinowicz and their series Look Around You.

"We try to make it very theatrical, and fun and musical and, y'know, weird," says Heidecker of the show. "It's sort of like a fan club meeting where we all get to be weird and hang out. People who go to the shows seem to find themselves to be a little in the minority amongst other people they know, so for them to be able to congregate with each other... it's a nice place maybe to meet a girlfriend." What kind of girlfriend you'd meet is another matter entirely.

• Tim & Eric's Awesome Show is at the Leicester Square Theatre, London, from July 26 to 29